Endometrial cancer is the most common gynecologic malignancy with an estimated 40,100 new cases expected in the United States in 2008. Uterine papillary serous carcinoma (UPSC) is an aggressive histologic subtype accounting for about 10% of all cases but almost 40% of endometrial cancer deaths. Unlike for the more common endometrioid endometrial carcinomas, the pathogenesis of UPSC is largely unknown. These cancers often present in advanced stages and exhibit poor response to chemotherapy. Effective and tailored treatment strategies are lacking. We performed a focused, real time PCR array comparing an endometrioid (Ishikawa) and a UPSC (SPEC2) cell line which revealed that the most highly expressed gene in SPEC2 over Ishikawa was the pro-metastatic oncogene synuclein-3 (SNCG). We also showed that SNCG mRNA and protein were highly expressed in SPEC2 versus endometrioid endometrial cancer cell lines. Similar expression data was obtained by Immunohistochemical staining. Finally, silencing of SNCG by shRNA caused a significant decrease in cell proliferation in SPEC2 cells and increased sensitivity of SPEC2 cells to paclitaxel induced apoptosis. SNCG is well studied in breast cancer where it correlates with advanced stage and aggressive disease as well as resistance to microtubule-disrupting agents. In this study, we will correlate SNCG expression in a series of 300 UPSC tumors and serum specimens with clinical and pathologic prognostic factors, response to chemotherapy, and outcomes in UPSC patients. Since SNCG was first described in breast cancer and a link between breast cancer and UPSC has long been suspected, we will also investigate SNCG expression in UPSC patients with a personal history of breast cancer. We will then study the molecular mechanisms by which SNCG influences proliferation, invasion, and sensitivity to antimicrotubule drugs in UPSC tumor cells by using various methods to inhibit SNCG in the SPEC2 cell line and compare results to two additional UPSC cell lines as well as a tet-inducible Ishikawa cell line overexpressing SNCG. We will also investigate the differential effect of other chemotherapeutics and targeted agents on the cell lines. In summary, we hypothesize that SNCG expression in UPSC is associated with its aggressive tumor phenotype, poor prognosis, and chemoresistance and that inhibition of its expression decreases the invasive and metastatic potential of the tumor and improves its sensitivity to microtubule targeting chemotherapy. SNCG may be a novel prognostic biomarker in UPSC correlating with advanced disease, decreased progression-free survival, and decreased response to standard chemotherapy. Additionally, SNCG could be developed as a novel therapeutic target. Its expression in UPSC could be used to hel guide our decision making in choosing the most effective chemotherapy. PUBLIC HEALTH RELEVANCE: By investigating the mechanism of action of SNCG in UPSC, we hope to lay the groundwork for a new therapeutic approach to UPSC that may ultimately have to be different than our current approach to treating all endometrial cancers. We believe that SNCG has potential as a biomarker for aggressive behavior in UPSC and may be able to help direct the choices of antineoplastic agents used to treat it. In addition, we will attempt to show that SNCG expression may link UPSC and breast cancer which would have implications regarding screening and prophylactic surgery in the two patient populations.